Showing papers by "Edson X. Albuquerque published in 2017"
TL;DR: The primary objectives of this article are to address the short‐ and long‐term neurological issues that have been associated with acute and subacute exposures of humans to OP insecticides, especially early in life, and to discuss the translational relevance of animal models of developmental exposure to OP Insecticides.
Abstract: Organophosphorus (OP) insecticides are pest-control agents heavily used worldwide. Unfortunately, they are also well known for the toxic effects that they can trigger in humans. Clinical manifestations of an acute exposure of humans to OP insecticides include a well-defined cholinergic crisis that develops as a result of the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that hydrolyzes the neurotransmitter acetylcholine (ACh). Prolonged exposures to levels of OP insecticides that are insufficient to trigger signs of acute intoxication, which are hereafter referred to as subacute exposures, have also been associated with neurological deficits. In particular, epidemiological studies have reported statistically significant correlations between prenatal subacute exposures to OP insecticides, including chlorpyrifos, and neurological deficits that range from cognitive impairments to tremors in childhood. The primary objectives of this article are: (i) to address the short- and long-term neurological issues that have been associated with acute and subacute exposures of humans to OP insecticides, especially early in life (ii) to discuss the translational relevance of animal models of developmental exposure to OP insecticides, and (iii) to review mechanisms that are likely to contribute to the developmental neurotoxicity of OP insecticides. Most of the discussion will be focused on chlorpyrifos, the top-selling OP insecticide in the United States and throughout the world. These points are critical for the identification and development of safe and effective interventions to counter and/or prevent the neurotoxic effects of these chemicals in the developing brain.
This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.
162 citations
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TL;DR: It is demonstrated that (2R,6R)-HNK inhibits synaptic NMDARs and subsequently elicits the same signal transduction pathway previously associated with N MDAR inhibition by ketamine, and that the effects of ( 2R, 6R)- HNK on intracellular signalling are coupled to NMD AR inhibition.
Abstract: Clinical data have demonstrated rapid and sustained antidepressant effects of ketamine, a noncompetitive NMDAR (N-methyl-daspartate receptor) antagonist1. Recently, Zanos et al.2 claimed that the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) is essential for the antidepressant effects of ketamine in mice in an NMDAR-independent manner, although no alternative mechanism was proposed, beyond unspecific activation of AMPAR (α -amino-3hydroxy-5-methyl-4-isoxazole propionic acid receptor)2. Here we report that (2R,6R)-HNK blocks synaptic NMDARs in a simi lar manner to its parent compound, and we show that the effects of (2R,6R)-HNK on intracellular signalling are coupled to NMDAR inhibition. These data demonstrate that (2R,6R)-HNK inhibits synaptic NMDARs and subsequently elicits the same signal transduction pathway previously associated with NMDAR inhibition by ketamine. There is a Reply to this Comment by Zanos, P. et al. Nature 546, http://dx.doi.org/10.1038/nature22085 (2017). In previous work3, we showed that ketamine exerts its antidepressant effects by blocking NMDARs at rest, which deactivates eukaryotic elongation factor 2 kinase (eEF2K), thereby dephosphorylating eukaryotic elongation factor 2 (eEF2) and resulting in a subsequent desuppression of brain-derived neurotrophic factor (BDNF) protein translation. This signalling pathway then potentiates synaptic AMPAR responses in the hippocampus through insertion of GluA1 and GluA2 subunits3–5. Notably, Zanos et al. show that (2R,6R)-HNK triggers the same intracellular pathway and downstream effects that we demonstrated for ketamine, namely inhibition of eEF2K, increased expression of BDNF, GluA1 and GluA2, and a form of synaptic potentiation in the hippocampus that is sensitive to AMPAR blockers3–5. The similarity between the molecular findings of ketamine and (2R,6R)-HNK led us to re-examine the potential involvement of (2R,6R)-HNK in NMDAR function. We assessed the effects of (2R,6R)-HNK in NMDAR-mediated miniature excitatory postsynaptic currents (NMDAR-mEPSCs) in cultured hippocampal neurons and compared its properties to the NMDAR antagonists 2R-amino-5-phosphonopentanoate (AP5) and ketamine. NMDA-mEPSCs were isolated in the presence of
27 citations
24 citations